Studies towards the Synthesis of (+)‐Dictyoxetane

Abstract The dolabellane‐type diterpene dictyoxetane represents a significant challenge to synthetic organic chemistry. Methodology directed towards the total synthesis of naturally occurring (+)‐dictyoxetane is reported. Catalytic asymmetric synthesis of the trans‐hydrindane ring system is achieved through chemoselective deoxygenation of the Hajos‐Parrish ketone. An alternative to the Garst‐Spencer furan annulation is developed for the synthesis of a 2,5‐dimethyl, tetrasubstituted furan, employing a tandem 5‐exo‐dig alcohol to alkyne cyclisation/aromatisation reaction as a key step. The (4+3) cycloaddition reaction of an oxyallyl cation with a tetrasubstituted furan is established on a cyclohexanone‐derived model system, and a range of related (4+3) cycloadditions investigated on a homochiral, trans‐hydrindane‐fused furan, where regio‐ and diastereoselectivity is required for the natural product synthesis. In an alternative (4+2) Diels‐Alder approach, a C2‐symmetric vinyl sulfoxide‐based chiral ketene equivalent is used to prepare oxanorbornenes with the same oxygen bridge stereochemistry found in the 2,7‐dioxatricyclo[4.2.1.03,8]nonane ring system of the natural product.


Introduction
Dictyoxetane 1, a dolabellane-type diterpene isolated in 1985 from the brown alga Dictyota dichotoma, [1,2] is one of the few natural products containing an oxetane ring (Scheme 1). The structure is comprised of trans-hydrindane 2 fused to the 2,7dioxatricyclo[4.2.1.0 3,8 ]nonane ring system 3, so far unique in nature. Although the biological activity of dictyoxetane is unknown, the Hoffmann group has prepared several model derivatives of the dioxatricyclic core which show promising anticancer activity. [3] In 2012, we reported a synthesis of the trans-hydrindane ring system 2 of dictyoxetane. [4] Racemic 7 was prepared in 4 steps from enone (�)-4, the Robinson annulation product of 2-methyl cyclopentanone with methyl vinyl ketone (Scheme 1). A phosphorus-mediated pinacol-like rearrangement of diol 5 was used to establish the requisite trans-ring junction stereochemistry. [5][6][7] Our methodology was subsequently adapted by Hugelshofer and Magauer to the asymmetric total synthesis of (+)-dictyoxetane using the chiral auxiliary approach developed by d'Angelo et al. [8,9] Enone (-)-4, derived from enamine 8, was estimated to be of � 80 % ee by comparison of optical rotation with literature values. Scalemic tertiary alcohol (-)-7 was converted in a further 8 steps to diene 9, which allowed for 7-membered ring annulation through a challenging ring-closing metathesis reaction to form trisubstituted alkene 10.
The late-stage formation of the 2,7dioxatricyclo[4.2.1.0 3,8 ]nonane ring system was achieved through sequential 4-exo-tet cyclisation to form oxetane 11, followed by a transannular 5-exo-trig cyclisation to form the tetrahydrofuran ring. In addition to being the first, and to date only, total synthesis of dictyoxetane, this work established the absolute stereochemistry of the natural product for the first time.
Hugelshofer and Magauer's approach to dictyoxetane differs from prior model syntheses of the dioxatricyclic core 3 in the order of formation of the oxygen heterocycles. Hoffmann, [3] Heathcock, [10] and Khlevin [11] first established the 8-oxabicyclo-[3.2.1]octane subunit via (4 + 3) cycloadditions [12] reactions of furans or (5 + 2) cycloadditions of oxidopyrylium betaines, then constructed the oxetane through intramolecular S N 2-like displacements of alkoxy nucleophiles at C-1 or C-3 (core 3 numbering) under basic or Lewis acidic conditions (Scheme 2). However, these model systems do not contain the additional 1,9-ring fusion found in the natural product, and attempts to build a hydrindane-like ring system onto an 8oxabicyclo[3.2.1]octane prior to oxetane formation were unsuccessful. [13] Building on these prior studies, we thought that the reverse strategy of annulation of the oxatricyclic ring system 3 onto trans-hydrindane 2 would be viable if: i) existing furan cycloaddition reactions to prepare 8-oxabicyclo[3.2.1]oct-6-ene ring systems could be extended to tetrasubstituted chiral furan 13; and ii) oxetane ring-closure could be effected from tetrasub-stituted alkene 12, or a derivative thereof (Scheme 3). Tetrasubstituted furan 13 was proposed to be formed from regioselective annulation of ketone 14. Scalemic 14 can be derived from the Hajos-Parrish ketone 15, available in high ee from an intramolecular asymmetric aldol reaction of 16, the Michael addition product of 2-methylcyclopentan-1,3-dione with methyl vinyl ketone. [14] Although 15 contains additional oxygenation compared with 4, we believed that the extra steps required to remove the unwanted carbonyl would be compensated for by the high enantioselectivity of the Hajos-Parrish ketone preparation, without significantly affecting overall yields.
We herein report synthetic studies towards dictyoxetane based on the retrosynthetic analysis shown in Scheme 3. Through this research, we have developed a large-scale, asymmetric synthesis of the key protected trans-hydrindanone 14 and a novel furan annulation sequence required for the conversion of cyclohexanone 14 to 13. We also report rare examples of (4 + 3) and (4 + 2) cycloaddition reactions on tetrasubstituted furans towards accessing key intermediate 12.

Asymmetric synthesis of trans-hydrindanone 24
Hajos-Parrish ketone 15 was prepared in two steps from commercially available 2-methylcyclopentan-1,3-dione in > 98 % ee and on > 100 g scale using the proline-catalysed aldol reaction under the conditions initially reported by Hajos and Parrish (Scheme 4). [14] Selective deoxygenation of the nonconjugated ketone in 15 has not been previously reported, although chemo-and stereoselective reduction to alcohol 16 is well known; [15] thus we elected to investigate a radical-mediated deoxygenation approach. [16] Initially, three thiono derivatives were synthesised (17,19, and 21) in high yield, but deoxygenation proved problematic (see Supporting Information for further discussion). Suspecting that the enone may be the issue, we explored acetalisation prior to deoxygenation. Both 19 and 21 proved compatible with the conditions required for acetalisation with concomitant double bond shift, [17,18] giving 20 and 22 respectively, but thionocarbamate 17 was acid-sensitive and lost the imidazole unit, forming the glycol thionocarbonate 18 in low yield.
Although we tested several radical deoxygenation conditions (H 3 PO 2 /Et 3 N/ACCN, [19] n Bu 3 GeH/ACCN, [20] n Bu 3 SnH/ACCN, [16] (Bu 4 N) 2 S 2 O 8 /NaOOCH [21] ), only (TMS) 3 SiH [22] afforded acetal 23 from 20 and 22 in acceptable yields. However, on larger scale, removal of the reaction by-products from 23, either by column chromatography or Nussbaumer et al.'s modified work-up, [23] proved difficult. Furthermore, we observed the partial conversion of the thiono group in both 21 and 22 to a carbonyl upon silica gel chromatography (see Supporting Information). [24] One solution to avoid silica gel was to recrystallise acetal 22, giving a 72 % yield over two steps from alcohol 16. However, we found the best solution was to not purify 21 or 22, and instead vacuum distil 23 to remove most of the impurities, including the by-products from the deoxygenation; recrystallisation of diol 5 then gave a 62 % yield over 4 steps from 16 with excellent purity. In contrast, xanthate 20 was less amenable to scale up, and could not be recrystallised like 22.
As in our previous racemic synthesis, [4] diastereoselective Upjohn dihydroxylation of acetal 23 to diol 5 and subsequent phosphorus-mediated pinacol-like rearrangement set the key trans ring junction stereochemistry. Stereoselective Grignard addition to ketone 6 gave the tertiary alcohol 7, which we initially chose to protect as a benzyl ether using benzyl bromide and either NaH/NaI/DMF or Hugelshofer and Magauer's KHMDS/THF conditions. [8] Acetal hydrolysis then gave 24. Overall, our new route allows for the asymmetric synthesis of transhydrindanone 24 in excellent enantiopurity over 11 steps and 34 % yield on multi-gram scale.

Modelling the furan annulation and (4 + 3) cycloaddition
Despite extensive research into the (4 + 3) cycloaddition reaction of allylic cations with furans, there is remarkably little precedent for the use of simple tetrasubstituted furans as dienes in these transformations. [25][26][27] We therefore elected to study the furan annulation -(4 + 3) cycloaddition sequence on a simpler cyclohexanone-based model system in the first instance. Transformation of cyclohexanone to dimethylfuran 28 in four steps has been previously reported based on a variant of the Garst-Spencer furan annulation to prepare a 2-thiosubstituted furan, followed by the sequential introduction of two methyl groups. [28] Preliminary investigation suggested that the Garst-Spencer approach was not suitable for delivering significant quantities of 28, and so we developed an alternative sequence that was more readily scalable (Scheme 5). Haloformylation of cyclohexanone under Vilsmeier-Haack conditions gave bromoenal 25, which was cross-coupled to trimethylsilylacetylene in a Sonogashira reaction to give enynal 26. [29] Addition of MeMgBr gave enynol 27, which underwent cyclisation-isomerisation to furan 28 upon treatment with tetrabutylammonium fluoride (TBAF). [30,31] Tetrasubstituted furan 28 proved to be an excellent diene for a (4 + 3) cycloaddition reaction with an oxygen-substituted oxyallyl cation using Hoffmann's conditions. [3b] Reaction of 28 with oxyallyl cation precursor 29 at À 78°C gave oxabicycles 30 and 31 as an inseparable 7.7 : 1 mixture of diastereomers in excellent overall yield over two steps from 27 (Scheme 5). The major stereoisomer was assigned as 30 on the basis of the greater downfield shift of the CÀ H adjacent to the OBn group compared to 31, consistent with an equatorial OBn and axial H on the 6-membered oxygen heterocycle as is typically observed in related 2-alkoxyl-8-oxabicyclo[3.2.1]octan-3-one ring systems derived from (4 + 3) cycloadditions of oxygen-substituted oxyallyl cations. [32,33]

Hydrindanone annulation and furan cycloaddition
Having established a new furan annulation and the feasibility of the (4 + 3) cycloaddition of an oxyallyl cation with a tetrasub- stituted furan, we attempted to apply the methodology on hydrindanone 24. Unexpectedly, the haloformylation conditions previously used to synthesise bromoacraldehyde 25 resulted in decomposition of 24, with no evidence of formation of 32 using either PBr 3 or POBr 3 . Treatment of 24 with POCl 3 afforded chloroenal 33 in 75 % yield, with regioselectivity consistent with reactions on related trans-hydrindanones. [34] However, despite ample precedent for the cross-coupling of chloroenals and vinyl chlorides, the Sonogashira reaction with trimethylsilylacetylene failed to deliver 34 under a range of conditions. [35] The failure of the bromoformylation reaction was surprising given the usually robust nature of the benzyl group. We envisaged access to the target furan 39 in an alternative manner via an acetylenic 1,3-diol, followed by cyclisation with dehydration. [36] A mixture of three 1,3-diols 36-38 was prepared in two steps from ketone 24 by a regio-and stereoselective aldol reaction with acetaldehyde to synthesise 35, [8] followed by a CeCl 3 -mediated addition of lithium (trimethylsilyl)acetylide to the ketone (Scheme 6). [37] Structural information for the 1,3-diols 36-38 was obtained via X-ray diffraction analysis (see Supporting Information). [38] The major compound 36 is derived from addition of the alkyne to the lower face of ketone 35. Diol 37 results from alkyne addition from the upper face, while 38 is derived from the minor aldol product. Unfortunately, attempts to cyclise major diol 36 to furan 39 under a range of conditions, including KO t Bu, [31] Pd II , [30,39] Ag I , [40] HCl, [39c] and Cu II , [39c,41] were unsuccessful.
With the failure to annulate benzyl-protected hydrindanone 24 to furan 39, we elected to reinvestigate the bromoformylation route with an alternative alcohol protecting group that could tolerate the Vilsmeier-Haack conditions. Following protection of tertiary alcohol 7 as a TIPS ether and acetal deprotection, haloformylation of ketone 40 with PBr 3 /DMF afforded bromoenal 41 in 75 % yield as a single regioisomer (Scheme 7). [29] Copper-free Sonogashira cross-coupling [35] followed by the addition of MeMgCl afforded an inconsequential diastereomeric mixture (3 : 1) of enynols 42. Conversion of 42 to furan 43 using TBAF/THF [30] produced multiple products, while Marshall's KO t Bu/ t BuOH conditions [31] only partially removed the TMS group before cyclisation. However use of K 2 CO 3 /MeOH/THF delivered furan 43 in an excellent 98 % yield.
With furan 43 in hand, methods for the construction of the 8-oxabicyclo[3.2.1]octane subunit were investigated. In contrast to prior model systems (Schemes 2 and 5), the cycloaddition of chiral furan 43 requires control over both facial selectivity and a means to regio-and stereoselectively incorporate an alcohol at C-3 (dioxatricyclic core 3 numbering). We anticipated the axially orientated methyl group at the hydrindane ring junction would influence facial selectivity, as was observed for the aldol reaction of 24, directing reaction through the lower face of furan 43.
We first elected to study (4 + 3) cycloaddition reactions of oxygen-substituted oxyallyl cations to directly introduce the requisite C-3 alcohol, as in our successful model study (Scheme 5). However, in contrast to the simpler furan 28, no reaction between furan 43 and the benzyloxyallyl precursor 29 was observed at À 78°C, and while warming the reaction to ca. À 40°C led to consumption of material, a complex mixture was produced, with no evidence for formation of target cycloadduct 44 (Scheme 8). Use of 2-(siloxy)acrolein 45 in a Sc(OTf) 3catalysed cycloaddition reaction [42] was more encouraging, leading to the formation of four cycloadducts 46-49. The structures of 46, 48, and 49 were determined by 2D NMR analysis, and showed the desired anti-relationship between the oxygen bridge and the adjacent silyloxy group, consistent with Harmata's results with 2,5-dimethylfuran and furan. [42] Cycloadduct 47 was not obtained in significant enough quantity to determine the absolute structure by NMR analysis, and was therefore inferred to be the last anti isomer possible. Despite the formation of cycloadducts, the modest combined yield (44 %) and lack of significant facial and regioselectivity made the siloxyacrolein chemistry unfeasible for total synthesis.

Chemistry-A European Journal
Research Article doi.org/10.1002/chem.202202429 To remove the C-3 alkoxy regio-and stereochemistry issue in the (4 + 3) cycloaddition reaction, we investigated the use of haloacetone oxyallyl cation precursors (Scheme 8). [43] After dehalogenation, a maximum of two ketones can be formed, resulting from addition to either face of furan 43. Treatment of 43 with 1,1,3-trichloroacetone 50 and Et 3 N gave an inseparable 1.4 : 1 mixture of ketones 52 in 80 % yield following zincmediated dehalogenation. Use of pentachloroacetone 51 as the coupling partner afforded a significantly more biased 4 : 1 mixture, albeit in lower overall yield. Although we were unable to unambiguously determine the stereochemistry of the major cycloadduct, we believe it is likely that reaction preferentially occurs from the lower face of furan 43 to deliver the desired oxygen-bridge stereochemistry: the analogous (4 + 3) reaction of silyloxyacrolein 45 with 43 is ca. 75 % selective for addition to the lower face (46 + 48 : 47 + 49). Unfortunately, selective αoxygenation of the mixture of ketones 52 could not be achieved using either an asymmetric deprotonation-silyl enol ether oxidation approach, [33] or through proline-catalysed αaminoxylation. [44] The poor reactivity of 52 is also reflected in its failure to form a simple enamine with pyrrolidine.
Tetrahalocyclopropenes undergo Diels-Alder reactions with furans followed by in situ ring-opening to form synthetically versatile oxygen-bridged tetrahalocycloheptadienes. [11,12,45] Treatment of furan 43 with tetrachlorocyclopropene (55) at room temperature gave a 1 : 1 inseparable mixture of cyclopropanes 57 and 58, derived from reaction with either face of the furan and assigned as exo adducts based on work by Wallerstein et al. (Scheme 8). [46] Use of tetrabromocyclopropene (56) at lower temperature gave a similar yield, paralleling early findings that bromide, whilst sterically more demanding, is more electronically activating in these dienophiles. However, no improvement in selectivity is seen on changing from 55 to 56. A tandem cycloaddition-thermal ring-expansion reaction sequence using 56 gave regioisomeric oxabicycles 59 and 60, each as a 1 : 1 mixture of facial isomers, in 95 % combined yield. Although the poor selectivity precluded further application in the synthesis of dictyoxetane itself, the possibility that the isomers could be converged to a 1 : 1 mixture of diketones 61 may be of future utility towards the synthesis of regio-and epimeric dictyoxetane analogues.
Our work on the formal (4 + 3) cycloaddition of furan 43 highlighted that, with the exception of pentachloroacetone 51, facial bias was low, suggesting that the axially orientated methyl group at the trans-hydrindane ring-junction alone was not capable of delivering the levels of selectivity required. Attempts to use the chiral oxyallyl cation precursor 62 to override substrate bias and control regioselectivity were unsuccessful due to poor furan reactivity at low temperatures. We therefore considered an alternative approach to intermediate 12 based on reduction of ketone 63, to be accessed through a regioselective one-carbon ring-expansion of oxanorbornenone 64 (Scheme 9). [47] Ketone 64 is the formal Diels-Alder reaction product of furan 43 with ketene, and hence offers the opportunity to influence facial and regioselectivity through reagent control, using an appropriate chiral ketene equivalent. Towards this goal, we herein report our preliminary investigations into the use of Aggarwal's C 2 -symmetric chiral ketene equivalent 65 as the dienophile in a Diels-Alder reaction with furan 43. Alkene 65 shows high reactivity in a range of cycloadditions, [48] and has recently been employed in natural product synthesis involving ring-expansion of the resulting ketone. [49] Treatment of furan 43 with enantiopure 65 at 0°C gave predominantly two compounds as an inseparable mixture in a 4 : 3 ratio and in 82 % combined yield (Scheme 10). While the structures could not be elucidated fully by NMR analysis, data were consistent with Diels-Alder adducts. Fortunately, X-ray crystal structures obtained on subsequent derivatives showed that 66 and 67 were regioisomers, both derived from reaction with the lower face of furan 43, producing the desired topfacing oxygen bridge. The bissulfoxide moiety was reduced with TFAA/NaI [48b] to give an inseparable mixture of dithiolanes 68 and 69. Attempted thioacetal hydrolysis under the literature conditions (CuCl 2 /SiO 2 with mild heating) [48a,b] resulted in the return of furan 43 as the exclusive product. Among several screened conditions (PIFA with and without NaHCO 3 , [50] NBS/ AgNO 3 /CaCO 3 , [51] I 2 /CaCO 3 [52] ), only MeI/CaCO 3 [53] afforded the oxanorbornenones 70 and 71, which were separable by column chromatography. X-ray crystallography [38] allowed for the unambiguous structural determination of both 70 and 71 and thus established that the Diels-Alder cycloaddition of 43 with 65 resulted in a mixture of regioisomers 66 and 67.

Conclusion
In summary, studies towards the asymmetric synthesis of (+)-dictyoxetane have been presented, based around the cycloaddition of a furan-annelated trans-hydrindane to assemble the carbocyclic core of the natural product. A high-yielding and scalable synthesis of enantiopure trans-hydrindane 24, a known intermediate in the reported asymmetric total synthesis of dictyoxetane, [8] was achieved through selective deoxygenation of the Hajos-Parrish ketone. A 4-step conversion of cyclohexanones to tetrasubstituted furans was developed as an alternative to a Garst-Spencer annulation -sequential dimethylation approach. Application of this methodology to a transfused hydrindanone required protection of an embedded tertiary alcohol as a TIPS ether, the corresponding benzyl ether proving to be incompatible with the Vilsmeier-Haack bromoformylation step. Tetrasubstituted furans were shown to participate in a range of (4 + 3) cycloadditions, but levels of regio-and stereoselectivity were modest using substrate control from the fused trans-hydrindane ring system. In an alternative approach based on reagent control, a C 2 -symmetric chiral ketene equivalent underwent (4 + 2) cycloaddition with excellent facial selectivity, but with low regioselectivity. Overall, we expect these studies to facilitate future research into the synthesis of dictyoxetane and simpler ring-fused analogues, and tetrasubstituted furans in general.